The Cell Polarity Protein MPP5/PALS1 Controls the Subcellular Localization of the Oncogenes YAP and TAZ in Liver Cancer

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 660 - 660

Published: Jan. 14, 2025

The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent liver oncogenes. Because gene mutations cannot fully explain their nuclear enrichment, we aim to understand which mechanisms cause YAP/TAZ activation in cancer cells. combination of proteomics functional screening identified numerous apical cell polarity complex proteins interacting YAP TAZ. Co-immunoprecipitation (Co-IP) experiments confirmed that membrane palmitoylated 5 (MPP5; synonym: PALS1) physically interacts After removing different MPP5 domains, Co-IP analyses revealed the PDZ domain plays a crucial role binding. interaction between cytoplasm cells was demonstrated by proximity ligation assays (PLAs). In human hepatocellular carcinoma (HCC) tissues, reduction expression observed, correlating accumulation Expression data analysis illustrated is inversely associated target signatures HCCs. Low levels define an HCC patient group poor clinical outcome. summary, facilitates exclusion TAZ cancer. This qualifies as potential tumor-suppressor explains how changes can foster tumorigenesis.

Language: Английский

---

Inverted apicobasal polarity in health and disease

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(5)

Published: March 1, 2024

Apicobasal epithelial polarity controls the functional properties of most organs. Thus, there has been extensive research on molecular intricacies governing establishment and maintenance cell polarity. Whereas loss apicobasal is a well-documented phenomenon associated with multiple diseases, less known regarding another type alteration - inversion In this Review, we provide unifying definition inverted discuss scenarios in mammalian systems human health disease which apical basolateral membrane domains are interchanged. This includes embryo implantation, monogenic diseases dissemination cancer clusters. For each example, consequences assessed, revealing shared outcomes, including modifications immune surveillance, altered drug sensitivity changes adhesions to neighboring cells. Finally, highlight alterations framework connect these core machinery explain roles disease. Based current state field, failure respond extracellular matrix (ECM) cues, increased cellular contractility trafficking defects likely account for cases

Language: Английский

---

Epithelial to Mesenchymal Transition in the Endometrium Mediated by HOXA10 drives Embryo Implantation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract Embryo implantation requires the breaching of endometrial luminal epithelium (LE) to facilitate invasion. In this study, we report that during implantation, LE cells undergo partial epithelial-to-mesenchymal transition (pEMT) specifically at sites. This pEMT in is critical, as vivo knockdown EMT transcription factor Twist 2 inhibits embryo implantation. Furthermore, observed a reduction expression HOXA10 Interestingly, HOXA10-hypomorphic mice and human epithelial (RL95-2) with ( KD) also acquire migratory phenotype vitro , suggesting loss drives epithelium. The KD have higher score differential genes associated cell migration TGF-β signaling pathways. We determined genome-wide occupancy sites identified 1,246 direct targets had significant roles EMT. Collectively, our findings suggest required maintain an state its activates mesenchymal resulting phenotype. adds member MET inducer team engage mutually inhibitory feedback loops directly or indirectly team. summary, study establishes critical step for reveals regulates process.

Language: Английский

---

The calcium pump PMCA4b promotes epithelial cell polarization and lumen formation

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: March 12, 2025

Abstract Loss of epithelial cell polarity and tissue disorganization are hallmarks carcinogenesis, in which Ca 2+ signaling plays a significant role. Here we demonstrate that the plasma membrane pump PMCA4 (ATP2B4) is downregulated luminal breast cancer, this associated with shorter relapse-free survival patients A B1 subtype tumors. Using MCF-7 cancer model show silencing results loss while forced increase PMCA4b expression induces polarization promotes lumen formation. We identify Arf6 as regulator endocytic recycling essential for PMCA4-mediated Silencing single pmca gene Drosophila melanogaster larval salivary gland destroys morphology suggesting conserved role PMCAs morphogenesis. Our findings point to controlling polarity, maintenance normal glandular architecture.

Language: Английский

---

A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancer

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 29, 2025

Abstract Cellular differentiation limits cellular plasticity allowing cells to attain their specialized functional characteristics and phenotypes, whereas loss of is a hallmark cancer. Thus, characterizing mechanisms underlying key discover new cancer therapeutics. We report novel antagonistic relationship between the prolactin (PRL)/prolactin receptor (PRLR) pathway YAP-CCN2 oncogenic in normal mammary epithelial breast that essential for establishing/maintaining acinar morphogenesis, cell-cell junctions intracellular localization apical-basal polarity protein complexes (Par, Crumb Scrib). Importantly, using CRISPR knockout PRLR MCF7, HR+ cells, further revealed negative PRL/PRLR critical suppressing luminal-to-basal stem-like lineage plasticity. Furthermore, clinical relevance this interplay was evaluated bioinformatics approaches on several human datasets, including samples from epithelium, cancer, 33 other types. This analysis positive correlation YAP suppressor Hippo co-expression gene network driving favourable patients’ survival outcomes The therapeutic potential also vitro MDA-MB-231 preclinical model triple-negative where treatment with PRL Verteporfin, an FDA-approved pharmacological YAP-inhibitor, alone or combination suppressed expression mesenchymal marker vimentin stem cell CD44 as well reduced Ki67 proliferative expression. Collectively, our results emphasize pro-differentiation role highlight promoting signaling while inhibiting can be exploited differentiation-based strategy

Language: Английский

---

Cell polarity: cell type-specific regulators, common pathways, and polarized vesicle transport

Leukemia, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Language: Английский

---

Frizzled receptors: gatekeepers of Wnt signaling in development and disease

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: May 1, 2025

Frizzled (FZD) receptors are a subset of G-protein-coupled (GPCRs), the largest class human cell surface and major target FDA-approved drugs. Activated by Wnt ligands, FZDs regulate key cellular processes such as proliferation, differentiation, polarity, positioning them at intersection developmental biology disease, including cancer. Despite their significance, FZD signaling remains incompletely understood, particularly in distinguishing receptor-specific roles across canonical non-canonical pathways. Challenges include defining ligand-receptor specificity, elucidating signal transduction mechanisms, understanding influence post translational modifications context. Structural dynamics, receptor trafficking, contributions also remain areas active investigation. Recent advances structural biology, transcriptomics, functional genomics beginning to address these gaps, while emerging therapeutic approaches—such small-molecule modulators antibodies—highlight potential drug targets. This review synthesizes current insights into examines ongoing controversies, outlines promising directions for future research development.

Language: Английский

---

Quantized multi-task learning for context-specific representations of gene network dynamics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

While often represented as static entities, gene networks are highly context-dependent. Here, we developed a multi-task learning strategy to yield context-specific representations of network dynamics. We assembled corpus comprising ~103 million human single-cell transcriptomes from broad range tissues and diseases performed two stage pretraining, first with non-malignant cells generate foundational model then continual on cancer tune the domain. learn cell types, tissues, developmental stages, diseases. leveraged cancer-tuned jointly states predict tumor-restricting factors within colorectal tumor microenvironment. Model quantization allowed resource-efficient fine-tuning inference while preserving biological knowledge. Overall, enables disease modeling that can contextual predictions candidate therapeutic targets for disease.

Language: Английский

---

Perspectives in collective cell migration – moving forward

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(12)

Published: June 15, 2024

Collective cell migration, where cells move as a cohesive unit, is vital process underlying morphogenesis and cancer metastasis. Thanks to recent advances in imaging modelling, we are beginning understand the intricate relationship between its microenvironment how this shapes polarity, metabolism modes of migration. The use biophysical mathematical models offers fresh perspective on migrate collectively, either flowing fluid-like state or transitioning more static states. Continuing unite researchers biology, physics mathematics will enable us decode complex biological behaviours that underly collective migration; only then can coordinated movement influences formation organisation tissues directs spread metastatic cancer. In Perspective, highlight exciting discoveries, emerging themes common challenges have arisen years, possible ways forward bridge gaps our current understanding

Language: Английский

---

Role of tight junction proteins in shaping the immune milieu of malignancies

Expert Review of Clinical Immunology, Journal Year: 2024, Volume and Issue: 20(11), P. 1305 - 1321

Published: Aug. 10, 2024

Introduction Tight junctions (TJs) and their constituent proteins play pivotal roles in cellular physiology anatomy by establishing functional boundaries within between neighboring cells. While the involvement of TJ proteins, such as claudins, cancer is extensively studied, studies highlighting interaction with immune system are still meager. Studies indicate that alterations cytokines cell populations can affect compromising barrier function exacerbating pro-inflammatory conditions, potentially leading to epithelial malignancy. Disrupted TJs established tumors may foster a pro-tumor microenvironment, facilitating tumor progression, invasion, epithelial-to-mesenchymal transition metastasis. Although previous literature contains many describing pathogenesis malignancies role modulating microenvironment just beginning be unleashed.

Language: Английский

---